Xenotransplantation has recently become the focus of intensive research as a potential solution to the shortage of human organ donors for transplantations. Pigs appear to be the organ donor of choice since pigs are relatively easy to breed and maintain and have anatomic and metabolic characteristics similar to humans. However, "xenozoonosis" (the inadvertent transmission of pathogens from animal organs into human recipients) is a major concern in xenotransplantation. Hepatitis E virus (HEV), the causative agent of hepatitis E is an important human pathogen worldwide and causes very high mortality, up to 20 percent, in infected pregnant women. Recently, a strain of HEV was identified in pigs in the United States (U.S.) and designated as swine HEV. It has been shown that swine HEV is ubiquitous in pigs and can infect non-human primates, and that a human strain of HEV isolated from a U.S. resident can infect pigs. Furthermore, HEV strains isolated from patients in the U.S. and in Taiwan are remarkably similar genetically to the swine HEV isolated from pigs in the U.S. and in Taiwan, respectively. These data raise a potential public health concern for zoonosis and thus, the proposed use of swine organs for human transplantation will have the potential to spread HEV in the general population. The hypotheses in this proposal are that hepatitis E is a zoonosis and swine are an animal reservoir for HEV, and that swine HEV infects humans and poses a potential public health risk for zoonosis and xenozoonosis. The objectives of this proposal are to assess the zoonotic and xenozoonotic risks of human infection by swine HEV, to determine the natural history of HEV in order to generate xenograft donor pigs free of HEV and prevent HEV zoonosis and xenozoonosis and, to develop diagnostic assays to screen for swine HEV in xenograft donor pigs. The proposed experiments are aimed at 1). evaluating zoonotic and xenozoonotic risks of human infection with swine HEV, 2). identifying and characterizing HEV strain(s) from wild-caught rats in or near pig farms that have pigs seropositive for HEV, 3). evaluating if laboratory rats can be experimentally infected by swine HEV, 4). identifying and characterizing field strains of swine HEV from different geographic areas and, 5). developing sensitive assays to screen for swine HEV in xenograft donor pigs. The information gained from the studies will significantly advance our understanding of the zoonotic and xenozoonotic risks of HEV infection and the natural history of HEV and, will be very useful in devising strategies to generate xenograft donor pigs free of HEV and to prevent HEV zoonosis and xenozoonosis.